舒林酸选择性诱导 GABA 能神经元自噬性凋亡，并改变斑马鱼的运动行为。

Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish.

机构信息

Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, 510006, China.

National Engineering Research Center for Tissue Restoration and Reconstruction, Key Laboratory of Biomedical Engineering of Guangdong Province, Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, Innovation Center for Tissue Restoration Reconstruction, South China University of Technology, Guangzhou, 510006, China.

出版信息

Nat Commun. 2023 Sep 2;14(1):5351. doi: 10.1038/s41467-023-41114-y.

DOI:10.1038/s41467-023-41114-y

PMID:37660128

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10475106/

Abstract

Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.

摘要

非甾体抗炎药是应用最广泛的药物类别之一，但它们在早期发育阶段的风险仍存在争议，尤其是在神经系统方面。在这里，我们利用斑马鱼幼虫来评估非甾体抗炎药的潜在毒性作用，结果发现舒林酸可选择性诱导斑马鱼幼虫大脑中 GABA 能神经元的凋亡。舒林酸暴露后，斑马鱼幼虫表现出过度活跃的行为。我们还发现 akt1 选择性地表达在 GABA 能神经元中，而 SC97（一种 Akt1 激活剂）和外源性 akt1 mRNA 可逆转舒林酸引起的凋亡。进一步的研究表明，舒林酸与视黄酸受体α（RXRα）结合，并诱导 GABA 能神经元自噬，从而激活线粒体凋亡途径。最后，我们验证了舒林酸可导致小鼠过度活跃和选择性诱导 GABA 能神经元凋亡。这些发现表明，舒林酸的过度使用可能导致早期神经发育毒性，并增加过度活跃的风险，这可能与 GABA 能神经元的损伤有关。